Age-related macular degeneration (AMD), also known as senile macular degeneration, is a senescent change of the retinal macular structure, and mainly is irreversible decrease or loss of vision caused by retinal pigment epithelial cells and retinal degeneration. The disease is clinically divided into dry (atrophic) AMD and wet (exudative) AMD, of which, wet AMD accounts for about 20% of the total number of AMD cases. But in western countries, wet AMD is the main reason of blindness for the aged. Intraocular abnormal vascular proliferation is one of the main causes of the occurrence and development of wet AMD, and blocking abnormal vascular proliferation is the basis of treatment of wet AMD. It may slow down or even prevent the disease process. Vascular endothelial growth factor (VEGF) is a secretory protein that can induce angiogenesis, increase vascular permeability, and cause inflammation. And these factors are closely related to the development of wet AMD. Therefore, in the development of medicaments for treating wet AMD, VEGF is a potential therapeutic target.
Recombinant fusion protein of human vascular endothelial growth factor receptor-antibody-human complement receptor 1 (hereinafter referred to as IBI302) is a macromolecule designed and developed for AMD disease based on the above mechanism. It is a new drug of State Category I with global intellectual property designed by the applicant. The route of administration is designed for intravitreal injection, and the dose is expected to be 0.5˜2 mg/eye.
Since 1982, after the introduction of the first recombinant drug (artificial insulin), more and more recombinant fusion protein drugs have been developed by protein engineering technology. Some of them have been accepted as conventional drugs. However, because such drug is a polypeptide or protein with large molecular weight, its performance is very unstable, prone to deterioration, and very likely to self-aggregation under high concentration of the protein. These unfavorable factors make a great challenge to making these drugs into stable, safe and effective formulations.
Recombinant fusion protein is a biomacromolecule, structure of which is very complex. During production and storage process, a variety of physical and chemical changes will occur in the expressed protein molecules. Physical changes are: adsorption, unfolding denaturation, aggregation and precipitation. Chemical changes are: deamidation, isomerization, oxidation and so on. These changes may influence the safety and effectiveness of the final product. Therefore, it is important to establish a suitable formulation to protect the stability and safety of the product.
IBI302 is a double-target specific fusion protein and is a new drug of State Category I. Due to its complex structure, the protein is unstable in chemical properties, and is prone to aggregation and the charge isomers are easily converted from the alkaline component to the acidic component. Therefore, there is still a need in the art to develop recombinant protein formulation for protecting the stability of the product.